Influence of Old Age on Risk of Lymph Node Metastasis and Survival in Patients With T1 Colorectal Cancer: A Population-Based Analysis

Abstract

Background We aimed at determining the influence of old age on lymph node metastasis (LNM) and prognosis in T1 colorectal cancer (CRC).

Methods We collected data from eligible patients in Surveillance, Epidemiology, and End Results database between 2004 and 2015. Independent predictors of LNM were identified by the logistic regression analysis. Cox regression analysis, propensity score-matched analysis and competing risks analysis were used to analyze the associations between old age and lymph node (LN) status, and to validate the prognostic value of old age on cancer-specific survival (CSS).

Results In total, 10092 patients were identified. Among them, 6423 patients (63.6%) had greater than or equal to 12 examined lymph nodes (LNs) (LNE ³12), and 5777 patients (57.7%) were of 65 years or older. The observed rate of LNM was 14.9 % (960 out of 6423). Logistic regression models demonstrated that tumor size ³3cm (odds ratio, OR = 1.316, P = 0.038), poorly differentiated (OR = 3.716, P <0.001), older age (OR = 0.633 for age 65–79 years, OR= 0.477 for age over 80 years, both P < 0.001), and negative CEA level (OR = 0.71, P =0.007) were independent prognostic factors. Cox regression analysis demonstrated CSS was not significantly different between elderly patients undergoing radical resection with LNE³12 and those with LNE <12 (HR= 0.865, P = 0.153), which were firmly validated after propensity score-matched analysis by a competing risks model.

Conclusions We found that tumor size<3cm, well/moderately differentiated, negative CEA level and adenocarcinoma in elderly patients with T1 colorectal cancer who were suitable for Local excision.

Introduction

Colorectal cancer (CRC) is among the most prevalent malignant tumors in most countries worldwide, and ranks the third as cancer-associated death in the US [1, 2]. In addition, the incidence of CRC is rising rapidly, greatly threatening the health of the elderly. T1 CRC is defined as tumor invasion into the submucosa (through muscularis mucosa but not penetrating into muscularis propria). TNM stage system reveals extremely similar survival for colon and rectal carcinoma, which, therefore, share the same staging system[3]. Lymph node metastasis (LNM) has been uncovered to range from 8 to 15% in T1 CRC [4]. Due to the substantial prognostic impacts of lymph node (LN) status, whether LN is involved is taken into consideration in clinical practice. To be specific, more comprehensive assessment of LN status is more likely to attenuate the risk of tumor understaging, while node-positive patients might be inaccurately identified as node-negative patients by insufficient evaluation, further leading to improper therapeutic approaches. Therefore, according to previous findings, most guidelines and consensus have recommended assessment of 12 or more LNs for acceptable staging of CRC [3]. However, the understaging mechanism has been argued in recent researches, which indicated limited improvement on survival by enhancing the number of sampled LNs by the efforts of professional associations as well as payers. Moreover, enhancing the number of sampled LNs during operation could not improve survival in CRC patients of 65 years and older [5]. For one thing, overtreatment in patients could cause harmful responses (including unnecessary biopsy, surgical resection, and other therapeutic interventions), particularly in the elder. For another thing, incomplete removal of positive LNs could enhance the risk of local recurrence, thereby leading to poor prognosis.

Advanced endoscopic techniques have been accepted as proper therapeutic interventions in T1 CRC patients following cautious selection and assessment [4, 6, 7]. Local excision in T1 CRC patients could decrease morbidity and further enhance life quality. In addition, careful local excision and cautious assessment of excluding risk factors (including LNM) could avoid unnecessary additional surgical intervention. Thus, patients at high risks of LNM should be identified, especially in elderly, to establish appropriate therapeutic strategies and simultaneously to minimize local relapse rate. Elderly CRC patients have a higher risk of death from non-tumor events than the overall population, including underlying diseases, infections, cerebrovascular and cardiovascular accidents, thereby decreasing cancer-related mortality rate. Thus, the precise prognostic prediction has become more difficult, and it is urgent to establish reliable and discriminative approaches for prognostic prediction in elderly patients.

To this end, with logistic regression model, propensity score-matching (PSM) analysis, and competing-risks approach, in this study, we explored the predictors for LNM and survival of elderly patients in T1 CRC by extracting eligible data from Surveillance, Epidemiology, and End Results (SEER) database.

Materials And Methods

Study population

The National Cancer Institute(NCI)supported SEER database, records data on tumor incidence and survival by covering almost 28% of population in the USA from diverse geographic regions (18 cancer registries) from 2004 to 2015. The collection and recoding of SEER data were performed using data items and codes on the basis of North American Association of Central Cancer Registries (NAACCR)[8]. Access to SEER database was obtained, and our study gained institutional approval. Clinicopathological characteristics of the selected patients in Table1.

Assessments and data acquisition

SEER*Stat software developed by the National Cancer Institute (Surveillance Research Program, National Cancer Institute SEER*Stat software 8.3.6; https://seer.cancer.gov). We conducted a comprehensive analysis of all primary CRC cases registered in the SEER database of the United States National Cancer Institute from 2004 to 2015. Patients were enrolled if: (1) they were 18 years or older; (2) at least one LN was sampled; (3) they underwent surgery of T1 CRC; (4) histological type included adenocarcinoma (8140), mucinous adenocarcinoma (MAC) (8480), and signet ring cell cancer (SRCC) (8490); (5) they were actively followed-up. Patients were eliminated if: (1) they had distant metastasis; (2) they received adjuvant radiotherapy; (3) they had more than one type malignancies, except those with CRC as the first diagnosed; (4) they had survival less than 1 month, which was mostly caused by surgical complications; (5) they only had a death certificate or were unaware whether operation was conducted.

Results

Baseline features

Of the 10092 eligible subjects receiving surgical resection due to T1 CRC, 5208 patients were male and the remaining 4884 were females. The median age at diagnosis was 67 years, ranging from 18 to 101 years, and the mean ± SD of age was 66.31 ± 12.34 years. The median follow-up was 69 months, ranging between 2 and 155 months. The median number of sampled LNs was 13, ranging from 1 to 90). The features of 3669 patients (36.4 %) with less than 12 examined lymph nodes (LNE < 12) and 6423 subjects (63.6%) with greater or equal to 12 examined lymph nodes (LNE≥12). Patients of or over 65 years were assigned into the elderly group. 5777 subjects (57.7%) were 65 years or older. 3546 subjects with greater or equal to 12 examined lymph nodes in elder patients. The observed rate of LNM was 14.9 % (960 out of 6423) in T1 CRC patients. The comparison of other clinicopathological characteristics of patients in two groups showed relevant imbalance (P < 0.001) (Table 1).

Risk factors of LNM

All patients underwent surgery, with at least 12 LNs sampled. To be specific, LNM risk was elevated in tumor size over 3 cm than tumors size under 1 cm, (OR = 1.316, 95% CI: 1.016–1.706, P = 0.038). Patients with negative CEA level had lower LNM risk than those with positive CEA level (OR = 0.710, 95% CI:0.553–0.911, P = 0.007). Moreover, elderly patients had decreased LNM risk (age 65–79 years: OR = 0.633, 95% CI: 0.498–0.804; age over 80 years: OR = 0.477, 95% CI: 0.349–0.652, both P < 0.001). Univariate and multivariate logistic regression models were employed for identification of risk factors of LNM, revealing that age, histology, tumor site, CEA level, tumor size and tumor grade were significant predictors for LNM. The detailed characteristics were displayed in Table 2. Furthermore, univariate and multivariate logistic regression models were employed for elder patients identification of risk factors of LNM, showed that Primary tumor site in rectum/Rectosigmoid was had higher LNM risk than cecum (OR = 1.449, 95% CI: 1.043–2.013, P = 0.027). Tumor grade, histology and CEA level were significant predictors for LNM. The detailed characteristics were displayed in Table 3.

PSM for elderly patients.

Adjustment of the observed effects in nonrandomized researches is critically involved in analyzing data in consideration of biased effect estimates due to confounding covariates. PSM was used to establish covariate balance, to minimize or even totally eliminate the confounding effects [11]. After PSM, 1733 of 2231 patients in LNE < 12 group could be matched with 2075of 3546 in LNE≥12 group at a 1:2 ratio, suggesting that the relevant bias on the observed characteristics was lost in two groups. Additionally, baseline characteristics of matched study population were displayed in Table 4.

Survival analysis before PSM in elderly patients

The mean CSS of elderly subjects receiving surgery with LNE≥12 was insignificantly different from those with LNE < 12 (142.91 moths [95% CI: 141.43-144.39] versus141.13 moths [95% CI: 139.36-142.89], P = 0.11) (Fig. 1A). In addition, multivariate analysis on CSS of patients undergoing surgery with LNE≥12 showed insignificant survival benefit (HR = 0.865, 95% CI: 0.709–1.055, P = 0.153). Consistently, univariate and multivariate Cox regression analysis demonstrated that gender, tumor size, tumor grade, CEA level, LNM, and marital status were significant prognostic indicators for OS and CSS in elderly T1 CRC populations (Table 5).

Survival analysis after PSM in elderly patients

In this cohort, mean OS of elderly patients receiving surgery with LNE≥12 was insignificantly different from those with LNE < 12 (107.79 moths [95% CI: 105.06-110.52] versus 104.47 moths [95% CI: 101.95-106.98], P = 0.118). The mean CSS of subjects undergoing surgery with LNE < 12 was insignificantly different from those with LNE≥12 (141.24 moths [95% CI: 139.41-143.07] versus 141.44 moths [95% CI: 139.43-143.44],P = 0.894) (Fig. 1B). Multivariate analysis revealed no significantly different OS or CSS between elder patients receiving surgery with LNE≥12 and those with LNE < 12 (OS: HR = 0.904, 95% CI: 0.816–1.001, P = 0.052; CSS: HR = 0.955, 95% CI: 0.772–1.181, P = 0.668). The characteristics were displayed in Table 6 in details.

Competing risk analysis after PSM in elderly patients

Both oncological and non-oncological factors could affect the survival outcomes of tumor patients. In other words, tumor patients may die from non-oncological cause [12]. To this end, a competing risks model was adopted to precisely assess the prognostic value of LNE on elderly T1 CRC patients, which could directly connect the impacts of risk factors with cause-specific cumulative incidence of mortality [13]. Consequently, the survival in LNE≥12 group was no longer than that in LNE < 12 group (Subdistribution hazard ratio, SHR = 0.891, 95% CI: 0.693–1.145, P = 0.37). Normal CEA level (SHR = 0.568, 95% CI: 0.385- 0.837P = 0.0043), tumor size > 3.0 cm (SHR = 2.289, 95% CI: 1.388–3.776, P = 0.026), poor differentiation (SHR = 1.664, 95% CI: 1.013–2.733, P = 0.044),and Primary tumor site in rectum(SHR = 1.772, 95% CI: 1.204–2.607, P = 0.0037) were significant prognostic indicators for elderly T1 CRC patients. Other detailed characteristics were shown in Table 7. CIF was additionally employed for assessing the possibility of death caused by oncological and non-oncological events [14]. Consequently, oncological and non-oncological death rates were insignificantly different between patients with LNE≥12 and those with LNE < 12(Fig. 2).

Discussion

Surgical resection and endoscopic submucosal dissection (ESD) are the main therapeutic for T1 CRC. Despite LN dissection during surgical intervention, 2.3–4% of T1 CRC patients still suffer from post-operative relapse [15]. Endoscopic resection of early-stage CRC including mucosal and submucosal cancer is advantageous, which could dramatically decrease postoperative morbidity, improves life quality, provide almost comparable long-term clinical outcomes compared with radical surgery[6, 16]. Notable, great caution should be given to endoscopic resection indications in T1 CRC in consideration of LNM in nearly one-tenth T1 CRC patients [17]. According to Japanese Society for Cancer of the Colon and Rectum (JSCCR)guideline, the presence of any of the four factors (lymphovascular invasion, budding, tumor invasion depth as well as poor histology) [18] indicates the recommendation of additional surgery for LN dissection. Except for its effect on prognosis, the benefit of surgical resection is limited, particularly for patients of advanced age or with severe comorbidities.

The risk factors for LNM were identified by logistic regression analysis. Patients with inadequate number of sampled LN were eliminated during selection process (the cutoff value was set at 12 on the basis that at least 12 LNs exams are generally required for precise pathological diagnosis [3]. In our study, LNM rate was 14.9 % (960 out of 6423), which was remarkably higher than previously reported in T1 CRC patients (about 10%) [17]. The inconsistency might be caused by our present inclusion criteria, that is, only patients receiving radical surgery were enrolled in our research. To further attenuate the risk of false negative LNM and downgrading after neoadjuvant chemoradiation, patients with inadequate LNs sampled and those undergoing preoperative radiotherapy were eliminated in our research, which could give rise to more reliable LNM rate than previous ones.

In the present population-based research, we comprehensively examined the predictors of regional LNM in T1 CRC patients undergoing surgery and having at least 12 LNs sampled. Histology, tumor grade, tumor size, CEA, race, primary tumor location and age were significant predictors for LNM. Mucinous carcinoma(MAC)and Signet ring cell carcinoma༈SRCC༉ are relatively rare pathological types of CRC, accounting for about 10–15% and 0.1–2.4% of all CRC cases, respectively [19]. As a distinct subtype, MAC and SRCC have been showed to be associated with higher risks of lymph node involvement in stage I and II colorectal cancer[20]. Here, we consistently showed higher LNM risk in patients with colorectal MAC and SRCC (OR = 1.695, 95%CI:1.286–2.235, P < 0.001 and OR = 2.006, 95%CI: 1.017–3.957, P = 0.045). In addition, the LNM risk was significantly lower in well-differentiated tumors than moderately or poorly differentiated or undifferentiated tumors. Consistent with previous findings in T1 rectal and colon cancer[21]. Furthermore, only tumor size ≥ 3 cm showed an elevated risk of regional LNM (OR = 1.316, 95%CI: 1.016–1.706, P = 0.038). Like other studies concerning colorectal cancer [21–23], Consistent with our discovered that tumor size was a predictive factor for the risk of LNM in T1 colorectal cancer.

Primary tumor site has long been demonstrated to influence LNM risk in CRC. However, the prognostic significance and LNM relevance of laterality in T1 CRC (mainly including left hemi-colon, right hemi-colon and rectum), has been explored, giving rise to controversial outcomes [24]. Therefore, the whole colorectal tract was divided into eight sections for to determine the possible correlation between tumor sites and diverse clinical variables. As a result, elder patients with rectum/rectosigmoid junction cancer had higher LNM risk than those with cecum cancer. The LNM risk in T1 rectal carcinoma has been showed to be as high as 15% [25, 26], declining to 8% in the left colon and 3% in the right colon [25]. Here, we report alike consequence, which suggests that carcinoma of the ascending colon is a significantly decreases the LNM risk, whereas rectum/rectosigmoid junction cancer significantly increases the LNM risk.

Consistent with previous results in T1 CRC [21], we also found older age as a significant negative predictor for LNM. To be specific, LNM risk of patients with 65–79 years and over 80 years declined to 0.63 and 0.47, respectively in comparison to those under 49 years (both P < 0.001). The survival of CRC patients is affected by diverse prognostic factors. Surgical resection, a major therapy for CRC, might be improper or unsafe for elderly patients with comorbidities. Instead, endoscopic resection has been proposed as a minimally invasive technique for precancerous lesions as well as early-stage CRC.

Survival analysis revealed that LNM was a significant prognostic indicator for CSS (HR = 1.755, 95%CI: 1.390–2.215, P < 0.001) but not for OS (HR = 1.063, 95%CI: 0.928–1.218, P = 0.380) in elderly patients. Meanwhile, LNE≥12 was a significant positive indicator for OS in comparison with LNE < 12 (HR = 0.834, 95%CI: 0.758–0.917, P < 0.001) but not for CSS. Nevertheless, after PSM adjustment, OS (HR = 0.904, 95%CI: 0.816–1.001, P = 0.052) or CSS (HR = 0.955, 95%CI: 0.772–1.181, P = 0.668) was not significantly different between LNE≥12 and LNE < 12 in. Moreover, univariate and multivariate Cox regression analyses also evealed tumor size, CEA level, race as well as marital status as significant indicators for OS and CSS.

In elderly tumor patients, various factors could cause the existence of right censoring, including loss of follow-up and no death, which do not prevent survival or death of patients. By contrast, when patients die from non-oncological causes during follow-up, the proportion of cause-specific death (CSD) is decreased. The application of right censored data using conventional regression survival analysis can lead to biases, generally causing overestimation of the possibility of CSD. Unfortunately, the above concern is frequently observed in prognostic prediction among the elderly, who are more vulnerable to frailty and comorbidities, and have elevated non-oncological death than other age group. Under this situation, competing-risk concept might be used to readily solve the problem[27]. For multivariate analysis, the two most commonly applied approaches include cause-specific hazard function and proportional subdistribution hazard function. The latter renders the covariant effects as better and more intuitive explanation, which can be properly used to calculate risk score and to construct clinical prediction model [28]. In terms of predictive factors, LNE≥12 was not significantly better than LNE < 12 (SHR = 0.891, 95% CI: 0.693–1.145 P = 0.37). Consistently with previous outcomes, we also find the negative correlation between tumor size ≥3cm and survival (SHR = 2.289, 95% CI: 1.388–3.776, P = 0.026), which is suggestive that tumor size could reflect tumor invasiveness to certain degree [29]. Furthermore,our study showed that Primary tumor site in rectum(SHR = 1.772, 95% CI: 1.204–2.607, P = 0.0037) were significant worse than cecum for elderly T1 CRC patients. It is correspond with the LNM risk in T1 rectal carcinoma higher than in the left colon or in right colon[25, 26].Preoperative CEA and histology have been prevalently accepted as independent prognostic indicators for CRC, capable of effective prognostic prediction in CRC. Positive CEA level and poorly differentiated histology are independent influencing factors for CRC prognosis. The prognostic value of these variables is also reflected in our model.

In this population-based research, our findings are mainly based on real-world outcomes. Nevertheless, certain limitations must be acknowledged, which are mainly caused by the intrinsic defects of SEER dataset. Lymphovascular invasion, submucosal invasion depth as well as tumor budding are also likely to affect LNM risk, which, are unavailable in SEER database. In addition, selection biases are unavoidable in the retrospective analysis.

In summary, in this population-based analysis on T1 CRC patients after surgery, the decreased morbidity for local excision has to be weighed against the favorable outcomes. Tumor size < 3cm, well/moderately differentiated, negative CEA level and adenocarcinoma could be used to select proper elderly colorectal cancer patients for Local excision.

Declarations

Acknowledgements

The authors acknowledge the efforts of the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER database. The interpretation and reporting of these data are the sole responsibility of the authors. Key Laboratory of Tiagnosis and Treatment of Digestive SystemTumors of Zhejiang Province (2019E10020).Supported by Ningbo Clinical research Center for Digestive Syestem Tumors (Grant No.2019A21003)

Funding

No financial support was provided for this study.

Availability of data and materials

The dataset from SEER database generated and analyzed during the current study are available in the SEER dataset repository (https://seer.cancer.gov/).

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing Interests

The authors have declared that no competing interest exists.

Authors Contributions

H.Y., P.C. and Q.Z participated in the design of this project, interpretation of data, and drafting and critical revision of the article and provided final approval of the version to be submitted. H.Y. and B.Z., completed the data collection and analysis.

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